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Clinical Effect Durability of Ampreloxetine (TD-9855) for Treating snOH in Subjects With Primary Autonomic Failure

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ClinicalTrials.gov Identifier: NCT03829657
Recruitment Status : Recruiting
First Posted : February 4, 2019
Last Update Posted : September 4, 2019
Sponsor:
Information provided by (Responsible Party):
Theravance Biopharma

Brief Summary:
A Phase 3, 22-week, Multi-center, Randomized Withdrawal Study of ampreloxetine in Treating Symptomatic Neurogenic Orthostatic Hypotension in Subjects with Primary Autonomic Failure

Condition or disease Intervention/treatment Phase
Symptomatic Neurogenic Orthostatic Hypotension Drug: ampreloxetine Drug: Placebo Phase 3

Detailed Description:
Phase 3, multi-center, randomized withdrawal study to evaluate the sustained benefit in efficacy and safety of ampreloxetine in subjects with primary autonomic failures (MSA, PD, or PAF) and snOH. The study consists of 3 periods: (i) 16-week open-label (OL) treatment with ampreloxetine, (ii) 6-week randomized placebo-controlled treatment, and (iii) 2-week follow-up (only for patients who do not enroll in Study 0171 (long-term extension safety study)).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 258 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Open Label Extension followed by Randomized Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 3, 22-week, Multi-center, Randomized Withdrawal Study of TD-9855 in Treating Symptomatic Neurogenic Orthostatic Hypotension in Subjects With Primary Autonomic Failure
Actual Study Start Date : February 22, 2019
Estimated Primary Completion Date : February 2021
Estimated Study Completion Date : February 2021


Arm Intervention/treatment
Experimental: ampreloxetine (Open Label (OL))
Participants will receive ampreloxetine as a single, oral, daily dose of active drug for 16 weeks.
Drug: ampreloxetine
Oral tablet, QD (Daily)
Other Name: TD-9855

Experimental: ampreloxetine
After completing the OL, participants randomized to ampreloxetine will receive single, oral, daily dose of active drug for a further 6 weeks.
Drug: ampreloxetine
Oral tablet, QD (Daily)
Other Name: TD-9855

Placebo Comparator: Placebo
After completing the OL, participants randomized to Placebo will receive single, oral, daily dose of placebo for 6 weeks.
Drug: Placebo
Oral tablet, QD




Primary Outcome Measures :
  1. Change (worsening) from baseline in OHSA#1 at Week 22 [ Time Frame: 6-week randomized withdrawal period (Week 16 to Week 22) ]
    Score change from baseline on Question 1 of the Orthostatic Hypotension Symptom Assessment (OHSA ). Question #1 assesses dizziness, lightheadedness, feeling faint, or feeling like you might blackout.

  2. Worsening of disease severity as assessed by a change in PGI-S at Week 22. [ Time Frame: 6-week randomized withdrawal period (Week 16 to Week 22) ]

    Score change from baseline on Patient Global Impression of Severity (PGI-S). PGI-S assesses patient's impression of disease severity.

    PGI-S uses a 7 point scale ranging from 1 (Normal, not at all ill) to 7 (Extremely ill).



Secondary Outcome Measures :
  1. Change from baseline in OHSA#1 at Week 22 [ Time Frame: 6-week randomized withdrawal period (Week 16 to Week 22) ]
    Score change from baseline on Question 1 of the Orthostatic Hypotension Symptom Assessment (OHSA). Question #1 assesses dizziness, lightheadedness, feeling faint, or feeling like you might blackout.

  2. Change from baseline in OHSA composite score at Week 22 [ Time Frame: 6-week randomized withdrawal period (Week 16 to Week 22) ]
    Orthostatic Hypotension Symptom Assessment (OHSA) is an assessment of the severity of symptoms from low blood pressure.

  3. Change from baseline in OHDAS composite score at Week 22 [ Time Frame: 6-week randomized withdrawal period (Week 16 to Week 22) ]

    Orthostatic Hypotension Daily Activities Scale (OHDAS) is an assessment of how low blood pressure symptoms affect daily life.

    OHDAS is a 4 item assessment that uses an 11 point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference.


  4. Standing Systolic blood pressure (SBP) during orthostatic standing test at Week 22 [ Time Frame: Week 22 ]
    SBP taken during the standing portion of the orthostatic standing test.

  5. Change from baseline in percent of time spent in supine, sitting, and standing position as measured by a wearable device at Week 22 [ Time Frame: 6-week randomized withdrawal period (Week 16 to Week 22) ]
  6. Change from baseline in UPDRS at Week 22 [ Time Frame: 6-week randomized withdrawal period (Week 16 to Week 22) ]

    Unified Parkinson's Disease Rating Scale (UPDRS) is a clinical rating scale for Parkinson's Disease (PD). Outcome measure only applies to subjects with PD.

    UPDRS is made up of 6 parts. Only parts 2 & 3 (self-evaluation of daily activities & clinician scored motor evaluation) will be measured at Week 22


  7. Change from baseline in PDQ-8 at Week 22 [ Time Frame: 6-week randomized withdrawal period (Week 16 to Week 22) ]
    Parkinson's Disease Questionnaire-8 (PDQ-8) is an assessment for Parkinson's Disease (PD) subjects. Outcome measure only applies to subjects with PD.

  8. Change from baseline in UMSARS at Week 22 [ Time Frame: 6-week randomized withdrawal period (Week 16 to Week 22) ]
    Unified Multiple System Atrophy Rating Scale (UMSARS) is an assessment for Multiple System Atrophy (MSA) subjects. Outcome measure only applies to subjects with MSA.

  9. Change from baseline in COMPASS-31 at Week 22 [ Time Frame: 6-week randomized withdrawal period (Week 16 to Week 22) ]
    Composite Autonomic Symptoms Score-31 (COMPASS-31) is an assessment that provides a quantitative measure of autonomic symptoms. Outcome measure only applies to subjects with Multiple System Atrophy (MSA).



Information from the National Library of Medicine

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Ages Eligible for Study:   30 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria (For 0169 Completers Group):

  • Subject has completed 4 weeks of double blind treatment in Study 0169 (V6) and, in the opinion of the Investigator, could benefit from continued treatment with ampreloxetine. No minimum score of OHSA#1 is required to enter V1 of Study 0170.
  • Subject has a minimum of 80% study medication compliance in Study 0169.

Inclusion Criteria (For De Novo Group):

  • Subject is male or female and at least 30 years old.
  • Subject must meet the diagnostic criteria of snOH, as demonstrated by a ≥20 mm Hg (systolic) or ≥10 mm Hg (diastolic) within 3 min of being tilted-up ≥60o from a supine position as determined by a tilt-table test.
  • Subject must score at least a 4 on the OHSA#1 at V1.
  • For subjects with PD only: Subject has a diagnosis of PD according to the United Kingdom Parkinson's Disease Society (UKPDS) Brain Bank Criteria (1992).
  • For subjects with MSA only: Subject has a diagnosis of possible or probable MSA of the Parkinsonian subtype (MSA-P) or cerebellar subtype (MSA-C) according to The Gilman Criteria (2008).
  • For subjects with PAF only: Subject has impaired autonomic reflexes, as determined by absence of Phase IV BP overshoot after release of the Valsalva strain.
  • Subject has plasma Norepinephrine (NE) levels ≥ 100 pg/mL after being in seated position for 30 minutes.

Exclusion Criteria (For 0169 Completers Group):

  • Subject has a medical, laboratory, or surgical issue(s) deemed by the investigator to be clinically significant.
  • Subject has an uncooperative attitude or reasonable likelihood of non-compliance with the protocol.
  • Subject has a concurrent disease or condition that, in the opinion of the investigator, would confound or interfere with study participation or evaluation of safety, tolerability, or pharmacokinetics of the study drug.

Exclusion Criteria (For De Novo Group):

  • Subject has a known systemic illness known to produce autonomic neuropathy, including, but not limited to, diabetes mellitus, diabetes insipidus, diabetic neuropathy, amyloidosis, or autoimmune neuropathies.
  • Subject has a known intolerance to other NRIs or serotonin norepinephrine reuptake inhibitors (SNRIs).
  • Subject currently uses concomitant antihypertensive medication for the treatment of essential hypertension unrelated to autonomic dysfunction.
  • Subject has used strong CYP1A2 inhibitors or inducers within 7 days or 5 half-lives, whichever is longer, prior to V1 or requires concomitant use until the follow-up visit.
  • Subject has changed dose, frequency, or type of prescribed medication for orthostatic hypotension (e.g., ephedrine, dihydroergotamine, or fludrocortisone), within 7 days prior to V1. These medications must be tapered off post-randomization. Tapering will follow the product's approved package insert (if applicable). Midodrine and droxidopa must be tapered off at least 7 days prior to V1.
  • Subject has known or suspected alcohol or substance abuse within the past 12 months (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR®] definition of alcohol or substance abuse).
  • Subject has a clinically unstable coronary artery disease, or has had a major cardiovascular or neurological event in the past 6 months.
  • Subject has used any monoamine oxidase inhibitor (MAO-I) within 14 days prior to V1.
  • Subject has a history of untreated closed angle glaucoma, or treated closed angle glaucoma that, in the opinion of an ophthalmologist, might result in an increased risk to the subject.
  • Subject has any significant uncontrolled cardiac arrhythmia.
  • Subject has a Montreal Cognitive Assessment (MoCA) ≤23.
  • Subject is unable or unwilling to complete all protocol specified procedures including questionnaires.
  • Subject had a myocardial infarction in the past 6 months or has current unstable angina.
  • Subject has known congestive heart failure (New York Heart Association [NYHA] Class 3 or 4).
  • Subject has a clinically significant abnormal laboratory finding (e.g., alanine aminotransferase [ALT] or aspartate aminotransferase [AST] >3.0 x upper limit of normal [ULN]; blood bilirubin [total] >1.5 x ULN; estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, or any abnormal laboratory value that could interfere with safety of the subject).
  • Subject has demonstrated a history of lifetime suicidal ideation and/or suicidal behavior, as outlined by the Columbia Suicide Severity Rating Scale (C-SSRS)(Baseline/Screening Version). Subject should be assessed by the rater for risk of suicide and the subject's appropriateness for inclusion in the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03829657


Contacts
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Contact: Theravance Biopharma Call Center 1-855-633-8479 medinfo@theravance.com

Locations
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United States, Arizona
Banner Sun Health Research Institute Recruiting
Sun City, Arizona, United States, 85351
United States, New York
New York University Langone Health Recruiting
New York, New York, United States, 10016
United States, Texas
University of Texas Southwestern Medical Center Recruiting
Dallas, Texas, United States, 75390
United States, Washington
Inland Northwest Research Recruiting
Spokane, Washington, United States, 99202
Sponsors and Collaborators
Theravance Biopharma
Investigators
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Study Director: Medical Monitor Theravance Biopharma

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Responsible Party: Theravance Biopharma
ClinicalTrials.gov Identifier: NCT03829657     History of Changes
Other Study ID Numbers: 0170
2018-003941-41 ( EudraCT Number )
First Posted: February 4, 2019    Key Record Dates
Last Update Posted: September 4, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Theravance Biopharma, Inc. will not be sharing individual de-identified participant data or other relevant study documents.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Theravance Biopharma:
Symptomatic Neurogenic Orthostatic Hypotension
orthostatic hypotension
low blood pressure
hypotension
snOH
multiple symptom atrophy
MSA
Parkinson's disease
PD
pure autonomic failure
PAF
OH
REDWOOD
ampreloxetine
170
dizziness
fainting
blacking out
lightheadedness
norepinephrine
Additional relevant MeSH terms:
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Hypotension, Orthostatic
Pure Autonomic Failure
Hypotension
Vascular Diseases
Cardiovascular Diseases
Orthostatic Intolerance
Primary Dysautonomias
Autonomic Nervous System Diseases
Nervous System Diseases